Allogeneic hematopoietic cell transplantation (HCT) for treatment of patients with hematological malignancies frequently fails because of disease recurrence. Attempts at intensifying the preparative regimen have been limited by associated toxicities due to the non-specific nature of most conditioning agents. The overall goal of Project 3 is to overcome this limitation by delivering targeted therapy to sites of leukemic involvement to decrease the risk of relapse after HCT without increased toxicity. Using preclinical models we have shown that 131I-anti-CD45 antibody (Ab) can deliver targeted radiation to hematopoietic tissues, with two to three times more radiation delivered to marrow, up to 12 times more to spleen, and two to eight times more to lymph nodes as compared to liver, lung or kidney. This preclinical observation has been translated to human studies that have demonstrated the feasibility of combining targeted radiotherapy with ablative preparative regimens in younger patients and with non-ablative regimens in older patients. Additionally, we have demonstrated encouraging outcomes in younger patients with AML in first remission receiving matched related HCT using I31I-anti-CD45 Ab combined with busulfan (BU) and cytoxan (CY) conditioning. Finally we have developed an approach of pretargeting that, in animal models, promises even greater specificity using CD45 as a target. To further develop the promise of targeted radiotherapy for the treatment of human leukemia, we now propose to extend these preliminary observations with three specific aims. In Aim 1 we will extend our single-center Phase II study to a multi-center Phase II study to examine the feasibility and further define the efficacy of using 131I-anti-CD45 Ab combined with BU and CY in younger patients with first remission AML. In Aim 2 we will establish the MTD of 131I-anti-CD45 Ab combined with a non-myeloablative HCT conditioning regimen for older AML patients and extend this application to Phase II studies in order to estimate the efficacy of this approach. In Aim 3 using Project 1 as a platform, we will determine the optimal doses of the agents for a pretargeted RTF approach that can be combined with a non-myeloablative regimen in a Phase I trial to treat patients with relapsed or refractory AML, ALL, or high risk MDS. We anticipate that in later years these studies will allow us to carry out important Phase III studies in which allogeneic HCT approaches employing l31I-anti-CD45 Ab are compared to standard HCT methods. In collaboration with the other Projects of this application, these interventions hold high promise to ultimately enhance the prognosis for patients with acute leukemias and MDS by increasing the response and survival rates, while simultaneously minimizing toxicities.